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Abstract and Introduction

Abstract

Introduction: Use of the Bair Hugger forced-air patient warming system
during prolonged abdominal vascular surgery may lead to increased bacterial
contamination of the surgical field by mobilization of the patient's skin
flora.Methods: This possibility was studied by analyzing bacterial
content in air and wound specimens collected during surgery in 16 patients
undergoing abdominal vascular prosthetic graft insertion procedure, using the
Bair Hugger patient warming system. The bacterial colony counts from the
beginning and the end of surgery were compared, and the data analyzed using the
Wilcoxon matched pairs test.Results: The results showed not only that
there was no increase in bacterial counts at the study sites, but also that
there was a decrease (P < 0.01) in air bacterial content around the
patient and in the operating theatre after prolonged use of the patient warmer.
No wound or graft infections occurred.Conclusion: The use of this
warming system does not lead to increased bacterial contamination of the
operating theatre atmosphere, and it is unlikely to affect the surgical field
adversely.

Introduction

Forced-air patient warming systems, such as Bair Hugger (Augustine Medical
Inc., Eden Prairie, MN, USA), were developed in the 1980s and are acknowledged
as being the most clinically effective patient warming modality.[1,2]
The advantages of avoiding hypothermia for patients undergoing major surgical
procedures are well established, and include decreased blood loss (with
consequent reduction in blood product use),[3] wound
infection,[4] duration of intensive care and hospital stay
[5,6] and cardiac ischaemia,[7,8] and increased
survival.[6,9,10] However, a potential disadvantage is the risk for
bacterial contamination of the operating theatre environment. Prolonged exposure
of the patient to the exhaust of the warming blanket could potentially mobilize
their resident skin organisms into the theatre atmosphere, and thence into the
surgical field, possibly increasing the risk for prosthetic material infection.
This has not previously been investigated.

We studied whether use of the Bair Hugger patient warming system increased
bacterial contamination of the operating theatre and the surgical wound during
prolonged surgery.

Methods

Sixteen consecutive patients undergoing aortic surgery with prosthetic graft
insertion were prospectively studied. All vascular surgery was performed in a
standard positive pressure theatre. The Bair Hugger upper body blanket (model
522) was used for all patients. Bacteria sampling sites are shown in Fig. 1. Air
samples were taken using standard techniques from the theatre atmosphere (sites
A1-A3) and around the axillae (sites B1 and B2), where the exhaust air emerged,
using the Biotest RCS centrifugal air sampler and Biotest Hycon TC agar strips
(Biotest UK Ltd, Solihull, West Midlands, UK). A total of 160 l of air was
sampled in 4 min from each of these sites. Sterile swabs were used to take
specimens from the warming unit and hose (site C) and immediately plated onto
standard blood agar culture media. Further specimens were taken from the wound
edges with touch plates of blood agar (site D). Two readings were taken from
each site, one when the warming blanket was first applied at the start of the
operation and again at the end of the operation. All the culture media were then
incubated at 36°C for 24 hours. The number of bacterial colonies visible to the
naked eye on each of the agar strips and culture plates were then counted by
hand and recorded.

The duration of the operation was recorded. There were nine staff circulating
in the operating theatre: three surgeons, two anaesthetists, one operating
department assistant and three nurses. All patients had three doses of
intravenous antibiotics perioperatively. The data were analyzed using the
Wilcoxon matched pairs test.[11]

Results

Twelve male and four female patients were included in the present study.
Their mean age was 72.5 years (range 60-86 years). The mean duration of use of
the warming blanket was 234 min (range 180-270 min). From each site, the number
of bacterial colonies at the start of surgery was compared with that at the end
of the operation.

Results are shown in Table 1 and Table 2. All operating theatre air specimens (sites A1-A3)
exhibited a decrease in colony counts at the end of surgery (mean reduction
36.4%). The exhaust air (sites B1 and B2) colony counts also decreased at the
end of surgery, although the size of the reduction was much less (mean reduction
9.5%). In the Wilcoxon matched pairs test, the test statistic T equalled 0,
because the rank difference was negative for all specimens from sites A1-A3, and
B1 and B2. This indicates that there was a significant decrease in the colony
counts at the end of surgery as compared with the beginning (P <
0.01). All filter (site C) and wound specimens (site D) were sterile.

None of the patients developed postoperative wound or prosthetic infections
during a 6-month follow-up period.

In the present study bacteria were not typed; only the absolute numbers of
colonies cultured were counted. Typing was to be done only if there was an
increase in colony counts at the end of surgery, and this did not occur in any
of the patients studied.

Discussion

As indicated above, the benefits of maintaining normothermia in surgical
patients is well documented. It has been shown that the warming equipment itself
does not cause bacterial dispersal [12] but the role of patient flora
was not investigated and the study was not conducted in a true surgical setting.
This remained a concern in our unit, especially because some bacteria in wound
infections originated from the patients' skin.[13] The present study
did not show any increase in the mobilization and dispersal of patient resident
skin organisms. The exhaust air from beneath the surgical drapes, which had
passed over the patient's skin, showed a decrease in the number of bacterial
counts at the end of surgery, and this demonstrated that there was no increase
in air contamination associated with the Bair Hugger patient warming system.
Furthermore, it indicated that the warm air stream did not force circulation of
the patients' skin organisms. If the Bair Hugger were affecting the atmosphere
adversely, then the room air counts would also be expected to increase rather
than decrease. In fact, the colony numbers in room air and system exhaust were
reduced and this was consistent.

Although the study was not designed to evaluate other causes of bacterial
presence in the operating theatre, we feel that the higher count at the
beginning of surgery in room air may be due to the unrestricted movement of
personnel in and out of the operating room, with opening and closing of doors,
leading to increased air flow and turbulence. Toward the end of surgery,
movement of staff is much less and this may explain the fall in bacterial counts
seen as the air turbulence decreases.[14,15]

Conclusion

We conclude that the use of the Bair Hugger patient warming system during
prolonged abdominal surgery does not lead to increased bacterial contamination
of the operating theatre atmosphere, and it is therefore unlikely to cause
contamination of the surgical field.

Aug. 21, 2003 — Editor's Note: Earlier this week at New York–Presbyterian
Hospital, the first of 12 patients approved by the U.S. Food and Drug
Administration (FDA) for participation in a phase I trial received gene therapy
for severe Parkinson's disease via adeno-associated viral (AAV) vector-mediated
somatic cell gene transfer. Under stereotactic guidance, neurosurgeons infused
into the subthalamic nucleus (STN) 3.5 billion viral particles, each bearing a
copy of a human gene for glutamic acid decarboxylase, an enzyme needed for
production of the neurotransmitter gamma aminobutyric acid (GABA).

Opponents of this treatment point to earlier disasters in gene therapy
history, suggest that efficacy has not been demonstrated adequately in primates,
and express concern that viruses could replicate within the brain or shut down
neural transmission by overexpression of inhibitory proteins. Furthermore,
therapeutic alternatives such as deep brain stimulation (DBS) have been shown to
be effective.

Although the main goal of this phase I trial is safety rather than
efficacy, the investigators and their patients are hoping to see some benefit
within three months after surgery. To learn more about the implications and
expectations of this controversial therapy, Medscape's Laurie Barclay
interviewed co-investigator Matthew During, MD, DSc, a professor of molecular
medicine at the University of Auckland in New Zealand. Dr. During is founder and
consultant of Neurologix, Inc., a company that has an interest in
commercialization of gene therapy for neurologic disorders.

Medscape: What does the gene therapy procedure entail?

Dr. During: The surgery entails a stereotactic neurosurgical procedure
under local anesthetic. First, magnetic resonance imaging ([MRI] using a new
generation 3T machine) is used to image the target region, the subthalamic
nucleus (STN). However, because millimeter accuracy is required, during surgery
the STN is mapped using microelectrodes by recording from single neurons as the
electrode is slowly moved towards the STN using a microdrive. Once the signature
firing pattern of the STN is obtained, confirming that the electrode is in the
STN, the fine wire electrode is pulled out, leaving just the microelectrode
sheath through which a hair-thin (170 µm) hollow vitreous silica fiber is
inserted. Thirty-five µL containing 3.5 billion particles of the viral vector,
an AAV containing the human GAD gene (cDNA), is then infused at 0.5 µL/min
together with 15 µL 25% mannitol. After the 100-minute infusion period, the
delivery catheter is withdrawn and the wound closed.

Medscape: Based on animal models and other relevant data, what is the
rationale for this procedure?

Dr. During: The rationale is based on both animal experiments as well
as proof-of-principle human studies. We know largely from primate studies, but
also from human electrophysiological studies, that the STN is overactive in
Parkinson's disease, with increased burst and tonic firing of the neurons. This
is because the degeneration of midbrain dopaminergic neurons leads to loss of
the normal inhibitory drive onto the STN; hence, it is disinhibited or
overactive. If you lesion the STN or electrically silence it by using very high
frequency electrical stimulation, typically around 130 Hz in DBS, the symptoms
of Parkinson's are dramatically reduced. A colleague, Dr. Anders Lozano from the
University of Toronto, has published that the effects of DBS can be mimicked by
the local infusion of muscimol, a GABA agonist. These data suggest that
strategies to inhibit or dampen the firing of the STN should lead to clinical
improvement. Because drug infusion lasts only a few minutes and requires a pump
and a continuous supply of the drug, it is not a practical procedure.

DBS is effective; however, it is associated with an approximate rate of 30%
for adverse events, including infection, erosions, disconnects, battery
failures, and pain. This is in addition to the expense: $20,000 for the hardware
alone; the need for a second procedure carried out under general anesthesia for
implantation of the stimulator in the chest; as well as prolonged and repeated
programming time. We believe that if we could obtain similar results to DBS but
with a simple one-shot injection approach, with no hardware and under local
anesthesia, then this could be a considerable advance and make the 10% to 15% of
Parkinson's disease patients who could benefit from surgery more likely to
receive an effective therapy.

There is also some theoretical advantage of delivering the GAD gene to the
STN over DBS, as the GABA production and release occurs not only in the STN, but
in the major afferent pathway in the internal segment of the globus pallidus
(GPi), which is also disinhibited in Parkinson's disease. Hence, the gene
transfer into the STN leads to inhibition of both the STN and GPi, both of which
are targets for DBS. The critical animal experiments in support of this
hypothesis were published by our team in Science in October of 2002.

Medscape: How is the first patient doing after surgery?

Dr. During: He is doing great. He was discharged Aug. 20 from New
York–Presbyterian Hospital. He has had no fever and no complications. His MRI
done two days after surgery shows no inflammation or changes in the STN, just
trace evidence of the microelectrode track leading to the STN.

Medscape: What are the expectations for this phase I trial?

Dr. During: First and foremost, safety. In the best-case scenario we
would like to see some clinical benefit. This first patient has largely
unilateral disease, and we were limited by the FDA for this phase I study to
perform unilateral surgery only. The hope is to see clinical benefit even with
this lowest dose — the trial includes four patients in each of three dose
cohorts, in a traditional open-label, dose-escalation design. We are also
monitoring surrogate markers, including 2-deoxyglucose PET, which we believe
will be a good barometer of efficient gene transfer.

Medscape: What are the potential advantages and disadvantages of gene
therapy compared with DBS and other alternatives?

Dr. During: The major advantages are no hardware; the entire procedure
is carried out under local anesthetic; and ultimately we believe this approach
will prove safer than alternatives, including DBS. Although we used very precise
microelectrode mapping of the STN, in the future we believe that unlike DBS,
where placement is absolutely critical down to the millimeter, for gene transfer
we could obtain good results even if we were several millimeters from the
midtarget zone. Hence, this surgery could be carried out by general
neurosurgeons using simple MRI-guided stereotactic procedures. In addition, DBS
requires a lot of fiddling and involvement by the referring neurologist, who
needs to program the stimulator, and this is not always simple or
straightforward. The 30% adverse event rate associated with DBS is also not
trivial, and we believe this should be much less with the AAV gene transfer.

The disadvantages of gene therapy largely relate to the unknowns. Nathan
Klein is the world's first patient, and therefore we have no evidence of
efficacy. It just simply may not work or benefit him and other patients in the
future. Secondly, we are using a virus, which can potentially spread or be
transported retrogradely by axons projecting to the STN. If that happens, gene
expression could occur in regions outside the STN, and this might lead to
symptoms similar to those associated with the use of benzodiazepines, drugs that
act to facilitate GABA-ergic transmission. Specifically, we might see
drowsiness, sedation, and confusion, or potentially other neurologic deficits.

Finally, again because this is such a new approach, there may be untoward
effects that are entirely unpredictable. The vector may integrate at low
efficiency, and this could disrupt normal gene function, again leading to
neurologic signs and symptoms. We have not seen evidence of this in our animal
studies, including nonhuman primate safety testing, but the human brain is
different and hence there is always the risk of seeing something that was not
apparent in the animal studies.

Medscape: Are there other risks associated with gene therapy in general? How
do they relate to this specific application?

Dr. During: Several of the most concerning risks associated with gene
therapy are less likely with this specific application. The biggest concerns
relate to toxicity and immunogenicity of the virus, leading to a major
inflammatory response or an overwhelming immune reaction similar to that which
occurred with the unfortunate Jesse Gelsinger case. Here, we are using a
nonpathogenic virus, which does not elicit significant immune responses,
particularly when given directly into the brain, so we do not expect any
inflammatory or immunological responses.

The next major concern is whether the vector integrates, and thereby disrupts
the expression of normal genes, particularly those involving regulation of the
cell cycle. An example of this is the alarming cases of leukemia that occured in
two of the children enrolled in the French X-linked SCID protocol, in which high
titer retroviruses were used for gene delivery into hemopoietic stem and
progenitor cells. This event, we believe, is not a significant risk in our
current protocol because first we are not using retroviruses, but AAV. Although
AAV can integrate, they do so at a much, much lower frequency, and again, unlike
retroviruses, they have never been associated with an oncogenic event.

Moreover, in the target cells in our protocol, postmitotic neurons,
activation of oncogenes leads not to the formation of cancer, but to apoptosis
of the transduced cells. Hence, even in the worst-case scenario with activation
of an oncogene in the target brain region, the cells would die, not form a brain
tumor. Ablation of the STN is an experimental therapy of Parkinson's disease and
is carried out in places where the costs of DBS are prohibitive, and it shows
some efficacy. So this event would likely cause clinical benefit, not harm to
the patient.

Medscape: What do you envision as the future role of gene therapy in
Parkinson's disease and in other neurodegenerative disorders?

Dr. During: We believe that ultimately gene therapy will replace other
surgical approaches, not only to Parkinson's disease but also to epilepsy and
potentially to other neurologic disorders. There was much excitement earlier
this month about the Science paper on AAV gene therapy of amyotrophic
lateral sclerosis, for example. Those investigators also commented that they
plan to proceed to clinical trials. We envisage gene therapy being complementary
to drug therapy and part of mainstream medicine in the future.

Danil Hammoudi.MDhttp://sinoemedicalassociation.comthe
medical information for allThis is for educational purposes only. It is not
intended to replace consultation and examination by your physician or
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